Pathogenic Activation of Receptor Tyrosine Kinases in Mammalian Membranes

He, Lijuan; Hristova, Kalina

doi:10.1016/j.jmb.2008.10.036

Cited by 44 publications

(79 citation statements)

References 54 publications

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“…To measure this effect, we first quantified the bands corresponding to the highest molecular weight mature fully glycosylated FGFR3. For successful quantification, the loading of the gels was such that all the band intensities were within the so-called "linear range," where the staining intensities were proportional to the protein concentrations (23). To plot results for the three receptors on the same scale, the highest phosphorylation level observed for each receptor was assigned a value of 1.…”

Section: Figure 3 Effect Of the Truncated Receptors On The Phosphorymentioning

confidence: 99%

FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

Shobnam

Wimley

et al. 2011

Journal of Biological Chemistry

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The G380R mutation in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) causes achondroplasia, the most common form of human dwarfism. Achondroplasia is a heterozygous disorder, and thus the affected individuals express both wild-type and mutant FGFR3. Yet heterodimerization in achondroplasia has not been characterized thus far. To investigate the formation of FGFR3 heterodimers in cellular membranes, we designed an FGFR3 construct that lacks the kinase domain, and we monitored the formation of inactive heterodimers between this construct and wild-type and mutant FGFR3. The formation of the inactive heterodimers depleted the pool of full-length receptors capable of forming active homodimers and ultimately reduced their phosphorylation. By analyzing the effect of the truncated FGFR3 on full-length receptor phosphorylation, we demonstrated that FGFR3 WT/G380R heterodimers form with lower probability than wild-type FGFR3 homodimers at low ligand concentration. These results further our knowledge of FGFR3-associated bone disorders.The G380R mutation in fibroblast growth factor receptor 3 (FGFR3) transmembrane (TM) 2 domain has been linked to achondroplasia, the most common form of human dwarfism (1). Achondroplasia, characterized by short stature, is a common (1 in 15,000 live births) autosomal dominant disorder that interferes with the maturation of the cartilage growth plate of long bones (2-4). The affected protein, FGFR3, is a receptor tyrosine kinase. Its activation, manifested in the autophosphorylation of its kinase domain, involves lateral dimerization and binding of FGF ligands and heparan sulfate (5, 6). Ligand binding increases receptor activation by stabilizing the dimers and perhaps altering the dimer structure (7-11).In cellular studies, the G380R mutation increases FGFR3 phosphorylation in the absence of ligand and at low ligand concentration (12-15). The increase, which is the likely cause for pathogenesis, has been linked to an increase in the phosphorylation of the unliganded dimer (13). However, FGFR3 dimerization does not appear affected by the G380R mutation, as both the wild-type FGFR3 and the G380R mutant show very similar cross-linking and dimerization propensities (13).Achondroplasia is a heterozygous disorder, and thus the affected individuals express both wild-type and mutant FGFR3. In this paper, we address the question whether mutant FGFR3 receptors heterodimerize with the wild type. Currently, the answer to this question is unknown. Most studies of FGFR3 activation thus far have focused on FGFR3 homodimers, because the detection of heterodimers is challenging. When both wild-type and mutant FGFR3 molecules are present in cells, three different dimeric species can co-exist as follows: 1) wild-type homodimers, 2) mutant homodimers, and 3) wildtype/mutant heterodimers (16). These dimers will be indistinguishable in many experiments, and their abundance will depend on the respective expression levels and on the dimerization propensities, which are unknown. Furthermore,...

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Section: Figure 3 Effect Of the Truncated Receptors On The Phosphorymentioning

confidence: 99%

FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

Shobnam

Wimley

et al. 2011

Journal of Biological Chemistry

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“…Recently, the effects of the Ala391Glu and the Val664Glu mutations on receptor dimerization in mammalian cells were investigated using western blotting. 40 In this study, the activation of Neu and a Neu chimera consisting of the extracellular and intracellular domains of Neu and FGFR3 TM domain was measured, and the effect of the mutations on dimerization was determined. The authors developed a quantitative physical-chemical description of receptor activation in terms of dimerization free energies, and generated mathematical predictions of active fractions as a function of receptor expression.…”

Section: Structure Of Rtk Tm Dimersmentioning

confidence: 99%

“…60 Thus, in the future the role of RTK TM domains should be investigated within the context of fulllength RTKs. So far, differences in TM domain strengths of homodimerization have been assessed for the full-length Neu receptors in mammalian cells, 40 but the approach is yet to be applied to ligand-binding receptors.…”

Section: Juxtamembrane Domainsmentioning

confidence: 99%

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Receptor tyrosine kinase transmembrane domains

Hristova

2010

Cell Adhesion & Migration

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“…There are three important processes for FGFR activation, i.e., ligand binding, receptor ligand dimerization and intracellular phosphorylation of receptors [15]. The binding of FGF and FGFR also needs the participation of cofactors to enhance the bioactivity of FGF.…”

Section: Fgfmentioning

confidence: 99%

Effect of FGF/FGFR Signal in Fluid Shear Stress and Estrogen Regulating Bone Metabolism

Luo¹,

Yang²,

Sun³

2017

Mol Biol

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Estrogen and fluid shear stress (FSS) play an important role in bone metabolism, displaying a synergistic effect. Fibroblast growth factors (FGFs) are also of great importance in bone development before and after birth. FGFs regulate downstream signaling pathway by activating FGF receptors (FGFRs) to control the expression of bone tissue cells. This paper conducts a brief discussion of the effect of FGF/FGFR as well as fluid shear stress and estrogen in bone metabolism regulation.

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Pathogenic Activation of Receptor Tyrosine Kinases in Mammalian Membranes

Cited by 44 publications

References 54 publications

FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism

Receptor tyrosine kinase transmembrane domains

Effect of FGF/FGFR Signal in Fluid Shear Stress and Estrogen Regulating Bone Metabolism

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